There is a need for methods of protecting the heart from injury, which may occur due to ischemic incidents and during reperfusion following ischemia, and maintaining cardiac function at a predetermined level thereafter.
Clinically, ischemia-reperfusion may occur in the setting of cardiac surgery. In order to perform many surgical procedures it is necessary to interrupt coronary blood flow resulting in ischemia to the heart. This ischemia not only limits the time available for the surgical procedure, it can also result in contractile dysfunction upon restoration of coronary flow. This is not only a problem in the adult patient undergoing coronary artery bypass surgery (CABG) or other surgical procedures, it is also a significant clinical problem during surgical heart procedures to correct congenital heart defects in neonates.
Current therapies aimed at improving contractile function following cardiac surgery in adult, pediatric and neonatal patients often involve the use of inotropes (e.g., calcium, dopamine, epinephrine, ephedrine, phenylephrine, dobutamine) in an attempt to increase contractile function. Although inotropic agents such as dobutamine have been reported to increase myocardial stroke volume and work, they also have been reported to increase myocardial oxygen consumption, and therefore may not enhance mechanical efficiency (1). In fact, the potential for inotropes to increase oxygen consumption to a greater extent than contractile function has been termed an oxygen wasting effect (2, 3). Inotropic drugs are also reportedly associated with increases in intracellular calcium concentration and heart rate, which may also be potentially harmful, especially in hearts with impaired energy balance (4).
The present invention is directed to methods of maintaining and improving cardiac function during and following an ischemic event and during reperfusion by administration of dichloroacetate (xe2x80x9cDCAxe2x80x9d) in combination with an inotrope. According to one aspect the methods of the present invention improve cardiac functional recovery and metabolism after an ischemic event, such as surgical heart procedures (including cardiopulmonary bypass and congenital lesions) in patients, as well as cardiovascular disorders such as hemorrhagic shock, hypoxia and trauma.
According to an aspect of the present invention, combination therapy of DCA with inotropes will enable administration of a lower dose of inotrope needed to maintain contractile function post-surgery.
One aspect of the present invention is directed to a method of decreasing the amount of inotrope needed to maintain a predetermined level of cardiac function in a patient which comprises administering to said patient a cardioprotective amount of dichloroacetate (DCA). According to this aspect, DCA may be administered as a bolus of at least about 50 mg/kg. According to one embodiment, administration of the DCA bolus is followed by an infusion of about 12.5 mg/kg/hour DCA for at least about 24 hours.
According to another aspect of the present invention, provided is a method of maintaining cardiac function at a predetermined level in a patient after cardiac surgery and decreasing said patient""s need for inotropes which comprises administering to said patient DCA in a bolus of at least 50 mg/kg followed by infusion of at least about 12.5 mg/kg/hour for at least about 24 hours.
In an alternate aspect, the present invention provides an improved method of maintaining cardiac function at a predetermined level in a patient in need of treatment while decreasing inotrope requirements, wherein the improvement comprises administering DCA within 15 minutes of administering said inotrope.
In another aspect, the present invention is directed to a method of decreasing the inotrope score in a patient who has undergone cardiac surgery which comprises administering a cardioprotective amount of DCA.
Please note that while the present invention is not limited to a particular dose level of DCA, doses and dosing protocols are suitable for use according to the methods of the present invention include the following. According to one aspect, DCA is administered continuously and a plasma level of at least about 1 mM is maintained in the patient for at least about 24 hours. According to one embodiment, a plasma level of at least about 1 mM, alternatively from about 1 mM to about 2 mM is maintained. The plasma level is maintained for at least about 1 hour, alternatively at least about 24 hours. According to an aspect of this embodiment, DCA is administered as a bolus before beginning the continuous administration of DCA. Suitable bolus doses are at least about 50 mg/kg, alternatively at least about 100 mg/kg. Suitable dose ranges for the bolus include at least about 50 mg/kg, alternatively from about 50 mg/kg to about 100 mg/kg.
The present invention provides DCA and inotrope to be administered in combination with each other, as in a single solution comprising DCA and inotrope. This combination method of administration allows decreasing the inotrope score in a patient who has undergone cardiac surgery wherein DCA is administered in a cardioprotective amount. In a further aspect of the invention, the method entails the administration of a bolus of DCA as described herein followed by administration of the combination intravenously, such as by intravenous infusion.
According to another aspect of the invention, provided is a pharmaceutical combination comprising a cardioprotective amount of DCA and an inotrope, the inotrope may be present at a therapeutically effective concentration to provide a lower dose of inotrope than the dose of inotrope that would be therapeutically effective in the absence of DCA.
xe2x80x9cInotropexe2x80x9d or xe2x80x9cinotropic drugsxe2x80x9d refers to a class of pharmaceutical agents which increase the contractility of cardiac muscular action. Inotropes conventionally used to maintain cardiac function and contractility include dobutamine, epinephrine, dopamine, norepinephrine, phenylephrine, phentolamine, digoxin, amrinone, and other agents known to those in the art.